HIF1α-glycolysis engages activation-induced cell death to drive IFN-γ induction in hypoxic T cells

The role of HIF1a-glycolysis in regulating IFN-g induction in hypoxic T cells is unknown. Given that hypoxia is a common feature in a wide array of pathophysiological contexts such as tumor and that IFN-g is instrumental for protective immunity, it is of great significance to gain a clear idea on this. Combining pharmacological and genetic gain-of-function and loss-of-function approaches, we find that HIF1a-glycolysis controls IFN-g induction in both human and mouse T cells activated under hypoxia. Specific deletion of HIF1a in T cells (HIF1a–/–) and glycolytic inhibition significantly abrogate IFN-g induction. Conversely, HIF1a stabilization in T cells by hypoxia and VHL deletion (VHL–/–) promotes IFN-g production. Mechanistically, reduced IFN-g production in hypoxic HIF1a–/– T cells is due to attenuated activation-induced cell death but not proliferative defect. We further show that depletion of intracellular acetyl-CoA is a key metabolic underlying mechanism. Hypoxic HIF1a–/– T cells are less able to kill tumor cells, and HIF1a–/– tumor-bearing mice are not responsive to immune checkpoint blockade (ICB) therapy, indicating loss of HIF1a in T cells is a major mechanism of therapeutic resistance to ICBs. Importantly, acetate supplementation restores IFN-g production in hypoxic HIF1a–/– T cells and re-sensitizes HIF1a–/– tumor-bearing mice to ICBs, providing an effective strategy to overcome ICB resistance. Taken together, our results highlight T cell HIF1a-anaerobic glycolysis as a principal mediator of IFN-g induction and anti-tumor immunity. Considering that acetate supplementation (i.e., glycerol triacetate (GTA)) is approved to treat infants with Canavan disease, we envision a rapid translation of our findings, justifying further testing of GTA as a repurposed medicine for ICB resistance, a pressing unmet medical need We conducted whole transcriptome analysis (RNA-Seq) using total RNAs isolated from WT and HIF1a–/– T cells that were activated, under normoxia and hypoxia for 48h. cleavage under targets and release using nuclease(Cut&Run) data for the histone H3 modification H3K9Acetate